Insulin action is initiated by binding of the hormone to the cell surface insulin receptor (IR), which is activated as a tyrosine kinase and is then coupled to downstream signal transduction pathways. Concomitantly, the activated IR kinase is rapidly engaged in a sequential series of trafficking steps which include: micro-aggregation and lateral mobility to specialized domains of the plasma membrane, translocation to the cell interior, and finally trafficking within the cell. Presently, there are major gaps in our understanding of how the IR kinase is coupled to the trafficking and signal transduction pathways, and what role trafficking plays in the final insulin bioresponses. Accordingly, the overall objective of this proposal is to contribute to further understanding in this important and evolving area of investigation. The three specific aims to be pursued are to: 1) characterize the role of the IR juxta-membrane domain in differential engagement of signal transduction pathways and in interactions with the cytoskeleton, 2) investigate the role of trafficking of IR complexes in insulin's biological actions, and 3) identify and characterize adapter protein(s) that specifically interact with the IR internalization domain in mediating endocytic signaling.